Handbook of Genetic Counseling/Friedreich Ataxia

Friedreich Ataxia Contracting Acknowledge prior contact What do they know about Friedreich Ataxia? Do they have any questions? Etiology Slowly progressive ataxia with onset usually during adolescence Autosomal recessive inheritance Majority of cases caused by mutations in X25/FRDA gene Found on chromosome 9q13 <1% of patients who meet the clinical diagnostic criteria do not have an identifiable mutation in this gene 96% of patients with FRDA1 are homozygous for a GAA expansion in the X25 gene Normal alleles have 7-38 repeats Premutation alleles have 34-60 repeats Disease-causing alleles 66-1700 triplets GAA repeat length is unstable during germ line transmission: Maternal transmission gives both contractions and expansions Paternal transmission usually contracts repeat size but premutation alleles may expand in size Larger expansion size correlates with earlier onset of disease X25 gene codes for a protein called frataxin Found in inner mitochondrial membrane Putative iron transporter to regulate mitochondrial iron content Incidence and Carrier Frequency Population frequency of 2-4 per 100,000 Carrier frequency is 1/60-1/100 Clinical Features Obligatory diagnostic criteria: Progressive ataxia of gait and limbs Absent reflexes in legs Dysarthria Decrease in position sense and/or vibration in lower limbs Muscle weakness Motor nerve conduction velocity of >40 m/s with reduced or absent sensory nerve action potential Additional findings: Scoliosis Pes cavus Cardiomyopathy (66%) Usually in later stages of disease but may precede ataxia 2/3 of patients have abnormal EKG Optic nerve atrophy (25%) Sensorineural hearing loss (10%) Diabetes mellitus (10%) or glucose intolerance (20%) Natural history Ataxia usually develops in childhood or early teens Rate of progression is variable Mean age of loss of ambulation is 25 years Death usually occurs in 30's Cardiomyopathy Diabetes Pneumonia due to dysphagia 25% of patients have atypical findings Late-onset FRDA (LOFA) Approximately 15% of patients with FRDA Age of onset greater than 25 years of age Usually have repeat size smaller than 500 FRDA with retained reflexes (FARR) 12% of patients with FRDA Show brisk tendon reflexes for up to 10 years after disease onset FRDA with slowly progressive disease Disease progression slower in Acadian patients Age on onset and neurological manifestations similar Testing Molecular genetic testing can be used to identify mutations in X25/FRDA Shortest repeat length causing disease has not yet been determined for sure <1% of patients who satisfy clinical diagnostic criteria have no identifiable mutation Carrier testing Can be offered if two disease-causing mutations are identified in proband Alleles in premutation range may be transmitted unchanged or may expand Prenatal testing Clinically available for couples at 25% risk for having child with FRDA1 if both disease causing mutations are known DNA from amniocentesis at 16-18 weeks or CVS at 10-12 weeks can be analyzed Management No therapy is known to stop, delay, or reverse disease progression Future therapies may include: Drug therapy Gene therapy Other pathophysiology-based treatments Support Psychological support Prostheses, walking aids, and wheelchairs may help patients maintain an active lifestyle Physical therapy Speech therapy Orthopedic intervention for scoliosis and foot deformities Treatment of cardiac disease and diabetes Differential Diagnosis Demyelinating form of hereditary motor and sensory neuropathy type I (HMSNI or CMT1) Childhood symptoms may be similar Nerve conduction studies or DNA testing can determine definitively Vitamin E deficiency Should be considered in cases that don't show a GAA expansion Fulfill diagnostic criteria for FRDA but often have titubation and hyperkinesia Treated with Vitamin E supplements Other early onset ataxias present with different clinical findings Psychosocial Issues Feelings of guilt, anxiety Pregnancy issues: preimplantation genetic diagnosis, prenatal testing, possible pregnancy termination Discussion with other family members about risk, inheritance Disruption of work, school, social life for those affected Resources National Ataxia Foundation Phone: 763-553-0020 Email: naf@ataxia.org Muscular Dystrophy Association Phone: 520-529-5300 or 8-572-1717 Email: mda@mdausa.org Web: www.mdausa.org International Network of Ataxia Friends (INTERNAF) Web: internaf.org Resources Geneclinics. "Friedreich Ataxia" Web: www.geneclinics.org Online Mendelian Inheritance in Man. "Friedreich Ataxia" Web: www.ncbi.nlm.nih.gov Notes The information in this outline was last updated in 2001.